1. Field of the Invention
The present invention relates to therapeutic radiation oncology. More particularly, the present invention is directed to a radioactive X-ray source commonly referred to as a seed for interstitial implantation and to its method of manufacture.
2. Description of the Prior Art
Interstitial implantation of radiation-emitting materials for localized tumor treatment has long been recognized. The advantages of interstitial implants reside in their ability to concentrate the radiation on the tumor tissue while minimizing radiation exposure to normal tissue. Commonly used implantable materials include radioactive gold (gold-198) and radon-222. These materials are not without their shortcomings, however, since the highly penetrating radiation they emit not only subject normal tissue to more destructive radiation, but also make it difficult to adequately shield the administering personnel from the radiation emitted.
Another isotope commonly used for seed manufacture is iodine-125. The general effectiveness of these seeds has been described in several publications such as "The Use of Iodine-125 for Interstitial Implants, U.S. Department of Health, Education and Welfare Publication (FDA) 76-8022, Basil Hilaris et al, November 1975 and in U.S. Pat. No. 3,351,049.
U.S. Pat. No. 3,351,049 to Lawrence et al suggests the use of carrier-free palladium 103 as therapeutic seeds. Carrier-free palladium 103 (i.e., palladium 103 which does not contain palladium metal or other palladium isotopes) has never been incorporated in commercially-available tumor-treating materials because its short 17-day half-life makes it difficult to work with in view of the processing time required to isolate and purify the isotope. Perhaps of greater concern is the difficulty in producing a carrier-free palladium 103 seed which is safe in case of a failure of the seed outer container, that is, a seed from which the palladium 103 can not escape from its supporting medium inside the seed and migrate into the blood stream and/or normal tissue of patients treated in the event of such a failure. Numerous articles describe preparation of carrier-free palladium, from cyclotrons as, for example, W. M. Garrison, J. G. Hamilton, U.S. atomic Energy Commission, UCRL-1067 (1950); P. V. Harper, K. A. Lathrop, L. Baldwin, Y. Oda and L. Kryhtal, Pd-103: A New Isotope for Interstitial Implantation at Operation, Annals of Surgery, 148 p. 606 (1958); P. V. Harper, K. A. Lathrop and J. L. Need, source unknown (1961); V. I. Levin et al, Separation of Pd-103 without a Carrier, Otkrytiya, Izobret, 1969, 46(1), 170; V. I. Levin et al, Preparation of Carrier free Palladium-103 and a Radioactive Colloidal Palladium Composition for Medicinal Purposes, Radiokhimiya, 13(4), 622-7 (1971); P. Tarapcik and V. Mikulaj, Separation of Palladium 103 from Cyclotron Irradiated targets, Radiochem. Radioanal. Lett., 48 (1981) 1969, 46. In all instances, however, only small amounts of the isotope have been prepared, and then only for research purposes.
U.S. Pat. No. 4,702,228 does describe therapeutic seeds containing palladium 103 prepared by increasing the Pd-102 content found in palladium metal, i.e., by enriching palladium metal in palladium 102 and then by exposing it to a neutron flux so as to convert a small fraction of the palladium 102 to palladium 103. Seeds prepared in accordance with the process of this patent have been commercially successful, but are not without their shortcomings.
Unlike cyclotron palladium 103 production wherein carrier-free palladium 103 can be produced, nuclear reactor produced palladium 103 is not carrier-free. Palladium 103 is produced in a nuclear reactor by bombarding a target containing Pd-102 with neutrons (Pd-102(n, .gamma.) Pd-103). Since all of the Pd-102 nuclei are not converted and, since in addition, other naturally occurring isotopes of the element palladium are present in the target, Pd-103 cannot be produced in a carrier free state. In addition, since there are always other isotopes of Pd present, neutron activation products of these isotopes are produced as well. For example, the reaction Pd-108(n, .gamma.)Pd-109 also occurs and therefore Pd-103 from a reactor is always found in the presence of the radioisotope Pd-109 until the Pd-109 decays out of the matrix. Since Pd-109 is the same element as Pd-103, no chemical means are known to effect their separation. The presence of other nuclides of Pd, also leads to the production of significant activities of certain non-Pd radioisotopes, e.g. Pd-111, which decays to Ag-111, further complicating the radiochemical purification of the Pd-103 matrix. In contrast, carrier-free Pd-103 produced in a particle accelerator such as a cyclotron enters the purification scheme in a far purer state with essentially no unseparable radioisotopes present.
Another drawback of seeds produced in a nuclear reactor from Pd-102 enriched palladium is that for practical reasons soon to be apparent, one is obliged to use reactor produced Pd-103 at the specific activity level generated in the reactor without adjustment while the specific activity of cyclotron produced Pd-103 can be adjusted to provide for its economical utilization while at the same time providing for the production of a seed of predetermined therapeutic or apparent activity.
The specific activity of Pd-103 that can be produced in a nuclear reactor is determined by the enrichment of the Pd-102 target used, the neutron flux in the reactor and the length of exposure of the target to the neutron flux in the reactor. At this time, the highest enrichment of the Pd-102 available (Oak Ridge National Laboratories (ORNL)) has an isotopic purity of 77.9% Pd-102 with the remaining 22.1% made up of the other isotopes of Pd. The highest neutron flux available in the world is found in the ORNL HFIR facility where the level is approximately 2.6E15 neutrons/cm.sup.2 sec. This reactor runs in 21 day cycles with approximately 3 days between and due to the generation of extraneous isotopes such as Ag-111, the maximum practical irradiation time is two cycles. These factors taken together indicate the maximum specific activity that can be derived from a reactor target is approximately 345 Ci/g.
In contrast, the specific activity of carrier-free Pd-103 is 75,000 Ci/g.
The ability to adjust the specific activity of the Pd-103/palladium mixture onto the support allows the self absorption (the tendency of Pd or other nuclei of high atomic number to adsorb the low energy X-rays produced when a Pd-103 nucleus disintegrates) to be adjusted to a known value thus facilitating the manufacture of a seed with an accurately predetermined therapeutic or apparent activity. Such an adjustment procedure is not practical with reactor produced Pd-103 for two reasons: 1) because its specific activity, which is as illustrated above initially much lower than the carrier free Pd-103 produced in a cyclotron, can only be adjusted downward thereby increasing the amount Pd-103 and, because they are inseparable chemically, the amount of enriched Pd-102 that must be used per seed contrary to the best economic practice of the process and contrary to the conservation of the difficulty replaceable enriched Pd-102 and 2) the addition of palladium metal to reactor produced Pd-102 lowers the enrichment level of the Pd-102 contained in the seeds produced thereby reducing the utility of the Pd-102 /palladium mixture recovered from unused seeds, an essential element in the economical utilization of the enriched Pd-102 resource.
In view of the amounts of contaminating Pd-isotopes and non-Pd-isotopes present in Pd-103 produced in a nuclear reactor from Pd-102 enriched Pd and the constantly varying factors involved, e.g. neutron flux, extent of Pd-102 enrichment, exposure time, etc., it is difficult, if not impossible, to predict what the purity and/or specific activity of the resulting Pd-103 product will be for any given production run. Thus, Pd-103 production processes employing Pd-102 enriched Pd do not lend themselves to the design of a process for production of a reproducible product of predetermined activity.
A further shortcoming in seeds produced from Pd-102 enriched Pd resides in the fact that large amounts of Pd-nuclei remain which tend to shield the low energy X-rays released when the Pd-103 nuclei disintegrate. The practical result of this is that additional palladium material containing enriched Pd-102 and Pd-103 must be used to compensate for the X-rays absorbed by the palladium nuclei to attain the desired X-ray intensity outside the interstitial implant device.
Lastly, reactor produced Pd-103 from Pd-102 enriched Pd not only is costly because of the difficulty in enriching Pd metal in Pd-102, but poses environmental problems. Producing Pd-103 with a reactor requires the fission of uranium to produce the required neutrons. An adequate means to dispose of the resulting transuranic waste is still a subject of debate. The larger amounts of contaminant isotopes produced in a reactor target also present a disposal problem. Since electric power is the only requirement to make a cyclotron function and contaminant isotope production is much less, cyclotron produced Pd-103 has far less of an environmental impact.
It is apparent therefore that if it were possible to produce a seed of Pd-103 of sufficient purity and desired therapeutic activity via the cyclotron route that was also safe, that the advantages it would present over the presently commercially available Pd-103 seeds would be of immeasurable value.
It is an object of the invention, therefore, to provide a seed of Pd-103 of high isotopic purity and desired therapeutic activity that is also safe for use as an interstitial implant. By the term "safe" as used herein and in appended claims is meant a seed characterized by being non-toxic and having radioisotopically pure Pd-103 bonded to the support carrying same in a manner that preclude release therefrom, thereby substantially reducing the chances of the radioactive isotope leaking into the circulatory system of the patient.
Another object of the invention is to provide an interstitial seed composed of carrier free Pd-103 having added to it small amounts of palladium metal, which seed has an isotopic purity such that the ratio of the radiation absorbed dose to the patient from isotopes other than Pd-103 to that from Pd-103 is less than 0.01 and a specific activity of at least 2.5 Ci/gm.
A further object of the present invention is to provide a process for the production of a safe, Pd-103-containing seed substantially reduced in the self-shielding properties that characterize commercially-available Pd-103 seeds and which therefore enables use of smaller amounts of Pd-103 to achieve the desired X-ray intensity (therapeutic or apparent activity).
Yet another object of the invention is to provide a process for the production of Pd-103 seeds which does not present the purification difficulties encountered in present commercially available Pd-103 production processes.
A further object of the invention is to provide a process for the reproducible production of safe Pd-103 containing seeds of predetermined isotopic purity, self-shielding and therapeutic or apparent activity.
Lastly, the invention provides a process for Pd-103 seed production that is cheaper, does not require a difficulty replaced resource (enriched Pd-102) and that poses a reduced threat to the environment.